REACT: a randomized trial to assess the efficacy and safety of clazosentan for preventing clinical deterioration due to delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage.

OBJECTIVE: Ischemic complications account for significant patient morbidity following aneurysmal subarachnoid hemorrhage (aSAH). The Prevention and Treatment of Vasospasm with Clazosentan (REACT) study was designed to assess the safety and efficacy of clazosentan, an endothelin receptor antagonist, in preventing clinical deterioration due to delayed cerebral ischemia (DCI) in patients with aSAH. METHODS: REACT was a prospective, multicenter, randomized, double-blind, phase 3 study. Eligible patients had aSAH secured by surgical clipping or endovascular coiling, and had presented with thick and diffuse clot on admission CT scan. Patients were randomized (1:1 ratio) to 15 mg/hour intravenous clazosentan or placebo within 96 hours of the aSAH for up to 14 days, in addition to standard of care treatment including oral or intravenous nimodipine. The primary efficacy endpoint was the occurrence of clinical deterioration due to DCI up to 14 days after initiation of the study drug. The main secondary endpoint was the occurrence of clinically relevant cerebral infarction at day 16 after study drug initiation. Other secondary endpoints included clinical outcome assessed on the modified Rankin Scale (mRS) and the Glasgow Outcome Scale-Extended (GOSE) at week 12 post-aSAH. Imaging and clinical endpoints were centrally adjudicated. RESULTS: A total of 409 patients were randomized between February 2019 and May 2022 across 74 international sites. Three patients did not start study treatment and were not included in the analysis set. The occurrence of clinical deterioration due to DCI was 15.8% (32/202 patients) in the clazosentan group and 17.2% (35/204 patients) in the placebo group, and the difference was not statistically significant (relative risk reduction [RRR] 7.2%, 95% CI -42.6% to 39.6%, p = 0.734). A nonsignificant RRR of 34.1% (95% CI -21.3% to 64.2%, p = 0.177) was observed in clinically relevant cerebral infarcts treated with clazosentan (7.4%, 15/202) versus placebo (11.3%, 23/204). Rescue therapy was less frequently needed for patients treated with clazosentan compared to placebo (10.4%, 21/202 vs 18.1%, 37/204; RRR 42.6%, 95% CI 5.4%-65.2%). A nonsignificant relative risk increase of 25.4% (95% CI -10.7% to 76.0%, p = 0.198) was reported in the risk of poor GOSE and mRS scores with clazosentan (24.8%, 50/202) versus placebo (20.1%, 41/204) at week 12 post-aSAH. Treatment-emergent adverse events were similar to those reported previously. CONCLUSIONS: Clazosentan administered for up to 14 days at 15 mg/hour had no significant effect on the occurrence of clinical deterioration due to DCI. Clinical trial registration no.: NCT03585270 (ClinicalTrials.gov) EU clinical trial registration no.: 2018-000241-39 (clinicaltrialsregister.eu).

Volatile sedation in neurointensive care patients after aneurysmal subarachnoid hemorrhage: effects on delayed cerebral ischemia, cerebral vasospasm and functional outcome.

BACKGROUND: Volatile anesthetics have shown neuroprotective effects in preclinical studies, but clinical data on their use after aneurysmal subarachnoid hemorrhage (aSAH) are limited. This study aimed to analyze whether the use of volatile anesthetics for neurocritical care sedation affects the incidence of delayed cerebral ischemia (DCI), cerebral vasospasm (CVS), DCI-related infarction or functional outcome. METHODS: Data were retrospectively collected for ventilated aSAH patients (2016-2022), who received sedation for at least 180 hours. For comparative analysis patients were assigned to a control and a study group according to the sedation used (intravenous vs. volatile sedation). Logistic regression analysis was performed to identify independent predictors of DCI, CVS, DCI-related infarction, and functional outcome. RESULTS: 99 patients with a median age of 58 years (IQR 52-65 years) were included. 47 patients (47%) received intravenous sedation, while 52 patients (53%) received (additional) volatile sedation with isoflurane (n=30, 58%) or sevoflurane (n=22, 42%) for a median duration of 169 hours (range 5-298 hours). There were no significant differences between the two groups regarding the occurrence of DCI, angiographic CVS, DCI-related infarction, or functional outcome. In a multivariable logistic regression analysis, the use of volatile anesthetics had no impact on the incidence of DCI-related infarction or the patients' functional outcome. CONCLUSION: Volatile sedation in aSAH patients is not associated with the incidence of DCI, CVS, DCI-related infarction or functional outcome. Although we could not demonstrate neuroprotective effects of volatile anesthetics, our results suggest that volatile sedation after aSAH has no negative effect on patient's outcome.

Systemic CRP (C-reactive protein) Predicts Cerebral Vasospasm and Delayed Cerebral Ischemia Following Aneurysmal Subarachnoid Hemorrhage (aSAH): A Retrospective Observational Study.

BACKGROUND: Aneurysmal subarachnoid hemorrhage (aSAH) is often complicated by cerebral vasospasm (CVS) and delayed cerebral ischemia (DCI), which significantly impact patient outcomes. The study aimed to investigate the predictive value of systemic serum biomarker levels for CVS and DCI following aSAH. METHODS: We retrospectively analyzed data for 450 aSAH patients admitted to University Hospital Düsseldorf between January 2011 and October 2021. Serum biomarkers were measured on admission. The occurrence of CVS and DCI was assessed based on clinical and radiological criteria. Multivariate logistic regression analysis was performed to determine the independent association of serum biomarkers with CVS and DCI. We compared the predictive values of various models using the area under the receiver operating characteristic (ROC) curve. RESULTS: Of the 450 patients, 126 (28.0%) developed CVS, 123 (27.3%) developed DCI, and 62 (13.8%) developed co-occurring CVS and DCI. Patients with CVS, DCI, or both had significantly higher admission CRP levels than those without these complications (P < 0.001). Elevated CRP levels were independently associated with an increased risk of CVS, DCI and co-occurring CVS and DCI (P < 0.05). CRP demonstrated a higher predictive value for CVS (area under the curve [AUC]: 0.811) and co-occurring CVS and DCI (AUC: 0.802) compared to DCI alone (AUC: 0.690). CONCLUSIONS: Our findings suggest that admission systemic CRP levels can serve as a more valuable predictor for developing CVS than DCI following aSAH. Incorporating CRP into clinical assessments may aid in risk stratification and early intervention strategies for patients at high risk of these complications.

Evaluating Ischemic Heart Disease in Women: Focus on Angina With Nonobstructive Coronary Arteries (ANOCA).

Ischemic heart disease (IHD) is common in women, and cardiovascular disease is a leading cause of morbidity and mortality. While obstructive coronary artery disease is the most common form of IHD, millions of women suffer from angina with nonobstructive coronary arteries (ANOCA), an umbrella term encompassing multiple nonatherosclerotic disorders of the coronary tree. The underlying pathology leading to ischemia in these syndromes may be challenging to diagnose, leaving many women without a diagnosis despite persistent symptoms that impact quality of life and adversely affect long-term cardiovascular prognosis. In the last decade, there have been significant advances in the recognition and diagnostic evaluation of ANOCA. Despite these advances, the standard approach to evaluating suspected IHD in women continues to focus predominantly on the assessment of atherosclerotic coronary artery disease, leading to missed opportunities to accurately diagnose and treat underlying coronary vasomotor disorders. The goal of this review is to describe advances in diagnostic testing that can be used to evaluate angina in women and present a pragmatic diagnostic algorithm to guide evaluation of ANOCA in symptomatic patients. The proposed approach for the assessment of ANOCA is consistent with prior expert consensus documents and guidelines but is predicated on the medical interview and pretest probability of disease to inform a personalized diagnostic strategy.

Use of dual intraventricular vasodilators for refractory cerebral vasospasm in a pediatric patient with traumatic subarachnoid hemorrhage: A case report.

DISCLAIMER: In an effort to expedite the publication of articles, AJHP is posting manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time. PURPOSE: Subarachnoid hemorrhage (SAH) is a rare but life-threatening clinical event for pediatric patients. Cerebral vasospasm is a common complication of SAH that often leads to poor outcomes. This case report describes the use of dual intraventricular (IVT) vasodilators in a pediatric patient. SUMMARY: An 11-year-old male presented with traumatic diffuse SAH and cranial vasospasm. Despite treatment with IVT nicardipine, intravenous (IV) milrinone by continuous infusion, enteral nimodipine, and intraarterial verapamil and milrinone given during digital subtraction angiography, transcranial Doppler (TCD) mean velocities continued to rise. IVT milrinone was then added to IVT nicardipine and IV milrinone. The combination of IVT nicardipine, IV milrinone, and rescue therapy with IVT milrinone was continued for a total of 7 days. TCD mean velocities decreased into the mild to moderate range within 2 days of the patient receiving this combined regimen and remained globally low thereafter. CONCLUSION: This case illustrates the potential benefit of using dual IVT vasodilators to improve outcomes for pediatric patients with refractory cerebral vasospasm.

Postoperative Symptomatic Cerebral Vasospasm: Requiring Attention Following an Uneventful Resection of an Epidermoid Cyst - A Case Report and Literature Review.

Cerebral vasospasm associated with epidermoid cyst can be caused by tumor content spillage, such as spontaneous rupture and postsurgical resection. Symptomatic cerebral vasospasm following the resection of an intracranial epidermoid cyst is a rare but serious complication that lacks a consensus on treatment. Case presentation: A 10-year-old girl underwent an uneventful complete resection of a left cerebellopontine angle epidermoid cyst. On the second postoperative day (POD 2), she exhibited reduced speech, confusion, and hyperventilation followed by hypocapnia. On POD 4, she developed right hemiparesis and dysphasia. Cerebral magnetic resonance imaging showed restricted diffusion areas in her left temporal and parietal lobes and the dorsal thalamus. Magnetic resonance angiograms confirmed narrowing of the proximal middle cerebral arteries, consistent with vasospasm. Conservative management, consisting of intravenous hydration and corticosteroid administration, proved effective in resolving her symptoms and radiologic vasospasm. On POD 8, the extensive restricted diffusion areas notably decreased in size. Her right hemiparesis was completely resolved, and her dysphasia gradually improved over time. At the 1-year follow-up, she exhibited moderate transcortical sensory dysphasia. To our knowledge, this study is the first to report on a pediatric case of symptomatic cerebral vasospasm following an epidermoid cyst resection. The combination of tumor content spillage and hyperventilation may contribute to the occurrence of cerebral vasospasm and subsequent ischemia. This complication should be acknowledged after a complete and uneventful resection.

The potential of disulfiram as a drug to improve the prognosis after the onset of subarachnoid hemorrhage.

Subarachnoid hemorrhage due to rupture of intracranial aneurysms has a poor outcome, making this disease being the social problem. Inflammation evoked by the increase in intracranial pressure and the clot in the subarachnoid space after the onset of SAH exacerbates neuronal death and vasospasm, resulting in the poor outcome and severe aftereffects. Here, FROUNT mediates CCR2 and CCR5 signaling as an intracellular molecule binding to these chemoattractant receptors which facilitate the migration of inflammatory cells, such as macrophages, in situ to trigger inflammation there. Animal model of subarachnoid hemorrhage was established in rats through intrathecal injection of autologous blood. The effect of the FROUNT inhibitor, disulfiram, on survival rate, neuronal death in hippocampus or vasospasm was then examined. The intrathecal administration of disulfiram significantly suppressed the infiltration of CD68-positive macrophages and myeloperoxidase-positive neutrophils toward the clot in the cistern in situ. In this condition, disulfiram ameliorated the death of animals after the onset of subarachnoid hemorrhage in rats. In addition, disulfiram suppressed both the two major events after subarachnoid hemorrhage, the neuronal death in hippocampus and vasospasm. The pharmacological inhibition of CCR2 and CCR5 signaling by disulfiram could thus be the therapeutic strategy to improve the outcome of subarachnoid hemorrhage.

Severe Coronary Vasospasms in Asymptomatic COVID-19.

Since the emergence of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in 2019, we have witnessed its multi-organ system involvement, not limiting itself to the lungs. We present a case of a patient with asymptomatic coronavirus disease 2019 (COVID-19) infection who developed ST-elevation myocardial infarction (STEMI) due to coronary artery vasospasm. The patient exhibited symptoms of acute coronary syndrome, elevated troponins, and electrocardiographic changes consistent with STEMI. He was found to have significant coronary vasospasm on angiography that responded well to nitroglycerin. This case highlights the potential cardiovascular complications of COVID-19 infection, even when asymptomatic, and the importance of considering vasospasm as a possible mechanism in patients presenting with acute coronary syndrome. We also elaborate on some potential pathophysiological mechanisms in which COVID-19 may lead to coronary vasospasm.

Outcomes following surgical clipping of re-ruptured previously untreated intracranial aneurysms.

Re-rupture of untreated intracranial aneurysm is a potentially life-threatening condition. Despite tremendous advances in the diagnosis and treatment of intracranial aneurysms, such events are not rare and continue to pose a management dilemma. In this study, we examined the clinical, radiological and treatment details of patients who underwent microsurgical clipping for re-rupture of previously untreated intracranial aneurysms. Re ruptures were categorized as early and late re ruptures (< or > 7 days of inter ictus interval respectively). Modified Rankin Score (mRS) was used for functional outcome assessment and logistic regression analysis was used to test the predictors of long-term outcome. Re-ruptured intracranial aneurysms comprised 5% (n = 32/637) of the aneurysm clippings done at our center in this time span. The mean mRS score at discharge and at last follow-up were 3 and 3.04 respectively. Twenty-four (75%) patients were alive at a mean follow-up of 36 months. Early re-ruptures were associated with worse mean mRS scores at discharge (3.9 vs 2.5, p = 0.03) including the perioperative deaths (n = 4, 12.5%). The functional status at discharge and a poor preoperative clinical grade predicted a poor long-term outcome. Therefore, the long-term outcomes are primarily dependent on the short-term outcomes and to a lesser extent, the clinical grade at presentation. Those presenting with poor preoperative clinical grade, especially in the setting of an early re rupture, have a very poor prognosis and do not benefit from surgery.

Letter to the editor: "Beyond nimodipine: advanced neuroprotection strategies for aneurysmal subarachnoid hemorrhage vasospasm and delayed cerebral ischemia".

This letter commends the article by Luzzi et al. on alternative neuroprotection strategies for aneurysmal subarachnoid hemorrhage (SAH). It highlights the pharmacological advantages of nicardipine, cilostazol, and clazosentan over nimodipine in managing cerebral vasospasm and delayed cerebral ischemia. Emphasizing the need for personalized medicine, it advocates for integrating genetic screening and advanced monitoring techniques to tailor treatments to individual patient profiles. This approach could significantly improve clinical outcomes by optimizing drug efficacy and minimizing adverse effects.

Do electrocardiographic changes induced during intracoronary vasospasm provocation testing reflect those during spontaneous angina episodes in patients with vasospastic angina?: a case series.

Background: According to the Coronary Vasomotor Disorders International Study (COVADIS) group, the ECG criteria supporting the diagnosis of vasospastic angina (VSA) in spontaneous episodes or induced during intracoronary spasm testing are similar. However, it remains elusive whether acetylcholine-induced ECG changes during epicardial spasms reflect ECG changes that occur during the height of a spontaneous episode. Case summary: We present four patients diagnosed with VSA during intracoronary spasm testing, of whom the ECG characteristics during spasm testing and a spontaneous angina episode are described. All patients have >90% coronary epicardial vasoconstriction in one or more vessels during acetylcholine provocation. ECGs at the height of a spontaneous episode and during acetylcholine-induced coronary spasm are found to be different in three out of four patients. Discussion: In patients with VSA, the ECG at the height of a spontaneous episode and during acetylcholine-induced coronary artery spasm may differ substantially. In patients with symptoms suspicious of VSA, every effort should be undertaken to obtain ECGs during the height of a spontaneous episode of angina pectoris and there should be a low threshold to perform intracoronary function testing.

"Spasms in Silence": A case of coronary vasospasm-induced ventricular fibrillation.

A 56-year-old man presented following an aborted cardiac arrest. His initial ECGs showed episodes of transient repolarization abnormalities. Coronary vasospasm can be a precipitant for ventricular arrhythmia in these patients, underpinning the importance of continuous ECG for accurate diagnosis and management.

Measurement of transcranial Doppler insonation angles from three-dimensional reconstructions of CT angiography scans.

Blood velocities measured by Transcranial Doppler (TCD) are dependent on the angle between the incident ultrasound beam and the direction of blood flow (known as the Doppler angle). However, when TCD examinations are performed without imaging the Doppler angle for each vessel segment is not known. We have measured Doppler angles in the basal cerebral arteries examined with TCD using three-dimensional (3D) vessel models generated from computed tomography angiography (CTA) scans. This approach produces angle statistics that are not accessible during non-imaging TCD studies. We created 3D models of the basal cerebral arteries for 24 vasospasm patients. Standard acoustic windows were mapped to the specific anatomy of each patient. Virtual ultrasound transmit beams were generated that originated from the acoustic window and intersected the centerline of each arterial segment. Doppler angle measurements were calculated and compiled for each vessel segment. Doppler angles were smallest for the middle cerebral artery M1 segment (median 24.6°) and ophthalmic artery (median 25.0°), and largest for the anterior cerebral artery A2 segment (median 76.4°) and posterior cerebral artery P2 segment (median 75.8°). The ophthalmic artery had the highest proportion of Doppler angles that were less than 60° (99%) while the anterior cerebral artery A2 segment had the lowest proportion of Doppler angles that were less than 60° (10%). These angle measurements indicate the expected deviation between measured and true velocities in the cerebral arteries, highlighting specific segments that may be prone to underestimation of velocity.